ANN ARBOR, Mich. — For decades, the primary strategy in the fight against advanced prostate cancer has centered on a single biological vulnerability: the androgen receptor. By starving tumors of the hormones they need to grow, clinicians have been able to extend the lives of countless patients. However, cancer is a master of adaptation, and for many men, the disease eventually finds a way to survive without the very receptor that once fueled its progression. When this happens, the cancer becomes significantly more aggressive and far more difficult to treat.
Researchers at the University of Michigan Rogel Cancer Center have now announced a significant breakthrough in understanding this transition. In a study published in the Journal of Clinical Investigation, the team identified a specific gene, PROX1, that plays a pivotal role in prostate cancer cells that have evolved past their reliance on the androgen receptor. Perhaps most importantly, the researchers discovered that this gene can be indirectly targeted using an existing class of drugs, offering a potential lifeline for patients facing the most lethal subtypes of the disease.
The discovery addresses a phenomenon known as lineage plasticity. In the context of oncology, lineage plasticity describes a process where cancer cells shed their original identity—in this case, that of a typical prostate cell—and take on new characteristics that allow them to evade standard therapies. As these cells move away from their dependence on the androgen receptor, they enter a continuum of alternate identities, often becoming what is known as "double-negative" prostate cancer or the even more aggressive neuroendocrine prostate cancer.
"Patients whose prostate tumors lose reliance on the androgen receptor do poorly," said the study’s senior author, Joshi J. Alumkal, M.D., the Wicha Family Professor of Oncology at the University of Michigan Rogel Cancer Center. "Our results suggest a therapeutic approach for patients whose tumors have undergone that shift."
The research, led by Zhi Duan, Ph.D., began by looking for the specific factors that trigger this dangerous cellular transformation. By examining tumor biopsies from patients whose cancer had already undergone lineage plasticity, the team sought to identify which genes were working overtime. Their analysis pointed toward PROX1 as the most significantly upregulated gene in these resistant tumors.
PROX1 is a transcription factor, a type of protein that acts as a master switch by dictating which genes are turned on or off within a cell. While it is known to help determine cell identity in healthy tissues, its role in the progression of prostate cancer had not been fully realized. To confirm their findings, the University of Michigan team examined hundreds of patient tumor samples across the entire spectrum of the disease. They found that PROX1 serves as an early marker of lineage plasticity, appearing even before the cancer has fully transitioned into its most resistant forms.
The study revealed a stark inverse relationship: as PROX1 levels rise, androgen receptor expression falls. In laboratory experiments, when the researchers artificially introduced PROX1 into prostate cancer cells, those cells began to shut down their androgen receptors, mimicking the transition seen in the most difficult-to-treat clinical cases.
"We think PROX1 is regulating the androgen receptor," Alumkal explained. "It may be one explanation for why the androgen receptor gets turned off when tumors undergo lineage plasticity and transition away from the typical glandular prostate cancer identity."
This shift in identity is a survival mechanism for the cancer, but the Michigan team discovered that it also creates a new vulnerability. When the researchers used genetic methods to eliminate PROX1 expression in both double-negative and neuroendocrine prostate cancer cells, the results were dramatic. The cancer cells stopped proliferating and began to die. This indicated that while the cells had escaped their need for the androgen receptor, they had become "addicted" to PROX1 to maintain their new, aggressive identity.
However, translating this discovery into a clinical treatment presented a classic hurdle in drug development. Transcription factors like PROX1 are notoriously difficult to target directly with medication because they often lack the deep, well-defined "pockets" that traditional drug molecules need to bind to. To find a workaround, the researchers looked at the "company PROX1 keeps"—the other proteins it interacts with to carry out its functions.
"We examined the proteins that bind to PROX1," Alumkal said. "Among the top partners were histone deacetylases, or HDACs. We felt like this was guilt by association. We hypothesized that HDACs might cooperate with PROX1 and that targeting HDACs might be like targeting PROX1."
Histone deacetylases are enzymes that influence how DNA is packaged within a cell, thereby controlling gene expression. Because HDACs are already known to play roles in various types of cancer, the pharmaceutical industry has already developed several HDAC inhibitors. A number of these drugs have already received approval from the U.S. Food and Drug Administration (FDA) for treating certain blood cancers, though they have not yet become a standard of care for prostate cancer.
When the Rogel Cancer Center team tested HDAC inhibitors on prostate cancer cells expressing high levels of PROX1, the results confirmed their hypothesis. The cells were highly sensitive to the drugs. Treatment with HDAC inhibitors effectively depleted the PROX1 protein within the cells, leading to tumor cell death. The effect of the drugs was nearly identical to the results achieved when the researchers genetically removed the PROX1 gene entirely.
This finding is particularly significant because it suggests that a class of drugs already available and safety-tested could be repurposed to treat a group of patients who currently have very few options.
"Our work implicates PROX1 as an important early driver away from androgen receptor dependence," Alumkal said. "HDAC inhibitors can block PROX1 and reduce survival of aggressive prostate tumor models that have transitioned away from androgen receptor reliance. Our results suggest this class of drugs should be prioritized for clinical trials in patients who have aggressive prostate cancer subtypes, for which there are few treatment options."
The implications of the study extend beyond just identifying a new drug target; it provides a clearer map of how prostate cancer evolves. By identifying PROX1 as an early marker, clinicians may eventually be able to predict which patients are at the highest risk of developing resistance, potentially allowing for earlier intervention with HDAC inhibitors before the cancer becomes fully untreatable.
The research was a massive collaborative effort involving a wide array of specialists and institutions. Co-authors on the study included Mingchen Shi, Anbarasu Kumaraswamy, Dong Lin, Dhruv Khokhani, Yong Wang, Chao Zhang, Fiana Flores, Eva Rodansky, Olivia A. Swaim, William K. Storck, Hannah Beck, Radhika A. Patel, Erolcan Sayar, Brian P. Hanratty, Hui Xue, Xin Dong, Zoe R. Maylin, Rensheng Wan, David A. Quigley, Martin Sjostrom, Ya-Mei Hu, Faming Zhao, Zheng Xia, Siyuan Cheng, Xiuping Yu, Felix Y. Feng, Li Zhang, Rahul Aggarwal, Eric J. Small, Visweswaran Ravikumar, Arvind Rao, Karan Bedi, John K. Lee, Colm Morrissey, Ilsa Coleman, Peter S. Nelson, Eva Corey, Aaron Udager, Ryan Rebernick, Marcin P. Cieslik, Arul M. Chinnaiyan, Joel A. Yates, Michael C. Haffner, and Yuzhuo Wang.
The scale of the project was matched by the breadth of its support. Funding for the research was provided by numerous National Institutes of Health (NIH) grants, including CA251245, CA282005, CA186786, P30CA046592, T90DE030859, GM147365, CA214955-01A1, CA274336, P50CA97186, and CA163227. Additional support came from several U.S. Department of Defense grants (W81XWH-22-1-0833, HT94252410252, W81XWH2110539), the Joint Institute for Cancer Research, the Prostate Cancer Foundation, the Canadian Institutes of Health Research, the Terry Fox Research Institute, the Canadian Cancer Society, the BC Cancer Foundation, the Smith Family Scholar Award, the Sheppard Family Foundation, the Benioff Initiative for Prostate Cancer Research, the Silver Family Innovation Foundation, the National Science Foundation, and the Institute for Prostate Cancer Research.
As the oncology community looks toward the next steps, the focus will likely shift to designing clinical trials that specifically enroll patients with the double-negative and neuroendocrine subtypes of prostate cancer. For the Rogel Cancer Center team, the hope is that by targeting the mechanisms of lineage plasticity, they can stop the "chameleon-like" behavior of prostate cancer and provide more durable outcomes for those facing the most aggressive forms of the disease.
